The broad, long-term objective of this project is to advance understanding of the functional and morphological organization of the hypothalamo-neurohypophysial system, which is responsible for the secretion of the hormones vasopressin and oxytocin. The system is studied primarily in vitro using a supraoptico-neurohypophysial explant from rats because stable intracellular recording are possible in this preparation, and because membrane properties and neurotransmitter actions are more easily studied with level of control over the extracellular fluid. This project will focus in large part on a detailed analysis of the similarities and differences in the morphology, membrane properties and neurotransmitter responsiveness of identified oxytocin and vasopressin neurons within the supraoptic nucleus in male and female rats as determined from intracellular recording and filling followed by immunocytochemical identification. The general hypothesis is that oxytocin and vasopressin neurons have distinguishable characteristics beyond their peptidergic phenotype, which underlie or facilitate their ability to express specific firing patterns during hormone release. Some differences may be sex-dependent, or in females, expressed selectively during the state of lactation, endowing these neurons with a functional plasticity to fit the demands of hormone secretion. The project also involves determining whether neurons in eh perinuclear zone of the supraoptic nucleus behave as interneurons and provide inhibitory synaptic inputs to neurosecretory neurons. The specific aims for the proposed research period are: 1) To continue the characterization of electrophysiological and morphological characteristics of identified oxytocin and vasopressin neurons, with the goal of understanding why some properties are shared and others are not between these two classes of neurosecretory cell; 2) To determine the mechanism by which the neuromodulator histamine selectively depolarizes the membrane and enhances the depolarizing afterpotential in vasopressin, but not oxytocin neurons; 3) To determine the nature and importance of GABA-mediated synaptic activity on oxytocin and vasopressin neurons. Vasopressin is very important in determining proper water balance in all mammals, including man, and dysfunctions in its control lead to many pathological conditions, such as diabetes insipidus and chronic hypernatremia. An understanding of the mechanisms controlling oxytocin neuron activity are important to the understanding of this hormone;s role in females during lactation and labor, and to its ill-understood in males.